Domvanalimab in combination with zimberelimab and FOLFOX (leucovorin, fluorouracil, and oxaliplatin) was active with no new safety signals in patients with untreated locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, according to findings from the phase 2 EDGE-Gastric trial (NCT05329766).

 In light of these findings, investigators initiated the phase 3 STAR-221 trial (NCT05568095), which is comparing domvanalimab plus zimberelimab and chemotherapy with nivolumab (Opdivo) plus chemotherapy in the same patient population.

“Domvanalimab is an [anti]-TIGIT monoclonal antibody,” Zev A. Wainberg, MD, a professor of medicine at UCLA and the codirector of the UCLA GI Oncology Program in Los Angeles, California, explained in an interview with 

®. “TIGIT is a checkpoint that is primarily on immune cells and blocking it leads to enhanced immune activation [and] also engages tumor-associated macrophages. The idea behind blocking TIGIT is that it works in concert with a PD-1 or PD-L1 inhibitor [such as] zimberelimab.”

EDGE-Gastric Provides Proof of Concept for Domvanalimab Combination

Arm A1 of EDGE-Gastric enrolled treatment-naive patients with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.

 Eligible patients also needed to have measurable disease per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. Patients with HER2-positive tumors were excluded. Enrollment was permitted irrespective of PD-L1 levels.

All patients received domvanalimab at 1600 mg and zimberelimab at 480 mg; both agents were administered every 4 weeks. FOLFOX was given every 2 weeks. Treatment continued until disease progression or unacceptable toxicity.

The coprimary end points of EDGE-Gastric were overall response rate (ORR) and safety. Secondary end points included overall survival (OS), progression-free survival (PFS), disease control rate, and duration of response (DOR); these end points were evaluated in PD-L1 expression subgroups. Pharmacokinetic and biomarker data were also collected as secondary end points.

At the March 12, 2024, data cutoff, findings from EDGE-Gastric presented during the 

 demonstrated that the confirmed ORR among all patients who received the combination (n = 41) was 59% (95% CI, 42%-74%), including a complete response (CR) rate of 7%. The median DOR was 12.4 months (95% CI, 9.9-not evaluable [NE]).

Patients with a PD-L1 tumor area positivity (TAP) score of at least 5% (n = 16) achieved a confirmed ORR of 69% (95% CI, 41%-89%) with a CR rate of 6%. These respective rates were 50% (95% CI, 29%-71%) and 4% among patients with a PD-L1 TAP of less than 5% (n = 24). The median DORs among patients with a TAP of at least 5% and less than 5% were NE (95% CI, 11.5-NE) and 10.2 months (95% CI, 4.0-12.4), respectively.

The median PFS in the overall population was 12.9 months (95% CI, 9.8-13.8) and the 12-month PFS rate was 58% (95% CI, 42%-74%). The median PFS values in the patient subgroups with TAP scores of at least 5% and less than 5% were 13.8 months (95% CI, 11.3-NE) and 11.3 months (95% CI, 5.5-13.8), respectively. The respective 12-month PFS rates were 69% (95% CI, 46%-92%) and 47% (95% CI, 25%-69%).

“EDGE-Gastric is the largest dataset [of] FOLFOX plus domvanalimab and zimberelimab in [this patient population],” Wainberg said. “[Data from] the study showed a very high response rate of 59% in the overall population, [which included] patients with a PD-L1 TAP of less than 5%. The median PFS [in the overall cohort] was 12.9 months. I believe these [efficacy] signals warrant further investigation.”

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) and TEAEs related to any study drug occurred at rates of 100% and 98%, respectively. Grade 3 or higher TEAEs were reported at a rate of 73%, including 15% that were related to domvanalimab/zimberelimab and 59% that were related to FOLFOX. Notably, no serious TEAEs related to domvanalimab/zimberelimab occurred; overall, serious TEAEs were reported in 37% of patients. TEAEs resulting in study drug discontinuation, dose modifications or interruptions, or death occurred in 66%, 85%, and 2% of patients, respectively.

The most common grade 1 or 2 TEAEs included nausea (59%), fatigue (27%), diarrhea (27%), and thrombocytopenia (27%). Common grade 3 or higher TEAEs included neutropenia (51%), anemia (12%), and thrombocytopenia (7%).

In May 2025, Arcus Biosciences announced that OS data from EDGE-Gastric will be presented at a medical meeting in the fall of 2025.

“There have been preceding data that [showed] some activity, both with FOLFOX plus domvanalimab and zimberelimab, as well as with other TIGIT antibodies in [patients with] esophageal cancers. We have seen some preliminary activity that justifies the need for a phase 3 trial,” Sam Klempner, MD, a medical oncologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School in Boston, said in an interview with 

STAR-221 Aims to Confirm Benefit of Domvanalimab Plus Zimberelimab and Chemotherapy

STAR-221 is an open-label, multicenter study that is examining domvanalimab and zimberelimab plus chemotherapy in approximately 1040 adult patients with treatment-naive locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma (

 Eligible patients must also have an ECOG performance status of 0 or 1 and at least 1 measurable lesion per RECIST 1.1 criteria. Those with HER2-positive disease, clinically significant cardiovascular disease, untreated, symptomatic, or actively progressing central nervous system metastases, or disease progression within 6 months of completion of neoadjuvant or adjuvant therapy are excluded from the study.

Patients will be randomly assigned 1:1 to the investigational or active comparator arm. In the investigational arm, patients will receive domvanalimab at 1600 mg and zimberelimab at 480 mg once every 4 weeks in combination with FOLFOX every 2 weeks or domvanalimab at 1200 mg and zimberelimab at 360 mg plus CAPOX (capecitabine and oxaliplatin) every 3 weeks. In the active comparator arm, patients will receive nivolumab at 240 mg and FOLFOX every 2 weeks or nivolumab at 360 mg and CAPOX every 3 weeks.

“The comparator arm is an active combination, and it’s probably our best standard for this patient population,” Klempner commented. “I don’t believe there is a more active control arm that could have been [selected], so that was not a barrier to accrual. The trial is fully accrued, and we’re awaiting the readout.”

The primary end point is OS. Secondary end points include PFS, ORR, DOR, safety, and time to first symptom deterioration according to the Functional Assessment of Cancer Therapy–Gastric subscale.

The estimated primary completion date is December 2026. In May 2025, Arcus Biosciences announced that the first data readout from STAR-221 is expected in 2026.

“If [STAR-221] meets its primary end point and shows a statistically significant and clinically meaningful improvement in OS, I believe [this regimen] would become the de facto standard of care in patients with newly diagnosed disease,” Wainberg said. “However, there will be some nuance in [terms of] which patients [are best suited for this regimen]. We acknowledge that checkpoint inhibitors should be used primarily in patients with a PD-L1 expression of greater than one. It will be important for us not just to prove that the study met its primary end point in the intent-to-treat [population], but also in the cohorts in which checkpoint inhibitors are the standard [of care].”

Janjigian YY, Oh DY, Pelster M, et al. EDGE-Gastric arm A1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting; May 31 to June 4, 2024; Chicago, Illinois. Abstract 433248.

A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT05568095

Arcus Biosciences reports first-quarter 2025 financial results and provides a pipeline update. News release. Arcus Biosciences. May 6, 2025. Accessed July 15, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Arcus-Biosciences-Reports-First-Quarter-2025-Financial-Results-and-Provides-a-Pipeline-Update/default.aspx

Klempner SJ, Shitara K, Sison A, et al. STAR-221: a randomized, open-label, multicenter, phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma. 

. 2023;41(suppl 16):TPS4206. doi:10.1200/JCO.2023.41.16_suppl.TPS4206

Articles

The combination of domvanalimab, zimberelimab, and FOLFOX demonstrated efficacy and manageable safety in untreated advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma in the phase 2 EDGE-Gastric trial. This led to the initiation of the phase 3 STAR-221 trial, comparing this regimen with nivolumab plus chemotherapy. The EDGE-Gastric trial showed a 59% overall response rate and a median progression-free survival of 12.9 months. The STAR-221 trial aims to confirm the benefits of this combination, with overall survival as the primary endpoint, and results are anticipated in 2026.

STAR-221 will evaluate domvanalimab plus zimberelimab and chemotherapy for the first-line treatment of patients with gastric, GEJ, or esophageal adenocarcinoma. 

Domvanalimab Plus Zimberelimab and Chemo Set for Phase 3 Study After Showing Efficacy in Untreated Upper GI Cancers

After displaying promising results in patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma in the phase 2 EDGE-Gastric trial (NCT05329766), the combination of the investigational anti-TIGIT agent domvanalimab, the PD-1 inhibitor zimberelimab (Sepalizumab), and FOLFOX (leucovorin, fluorouracil, and oxaliplatin) is being further evaluated in this patient population in the phase 3 STAR-221 trial (NCT05568095). Findings from the phase 3 study could further support the integration of TIGIT blockade into the management of upper gastrointestinal (GI) cancers, according to Sam Klempner, MD.

“There have been preceding data that [showed] some activity, both with FOLFOX plus domvanalimab and zimberelimab, as well as with other TIGIT antibodies in [patients with] esophageal cancers. We have seen some preliminary activity that justifies the need for a phase 3 trial,” Klempner, a medical oncologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School in Boston, said in an interview with 

Updated fingings from arm A1 of the EDGE-Gastric presented at the 

 showed that patients who received the combination (n = 41) achieved a median progression-free survival (PFS) of 12.9 months (95% CI, 9.8-13.8) and a 12-month PFS rate of 57.6% (95% CI, 41.7%-73.5%).

 The confirmed objective response rate (ORR) was 58.5% (95% CI, 42.1%-73.7%), including a complete response rate of 7.3%. The median duration of response was 12.4 months (95% CI, 9.9-not evaluable).

In the interview, Klempner discussed the rationale for investigating TIGIT blockade in combination with chemotherapy and anti–PD-1 therapy for patients with upper GI cancers;, the design of STAR-221; and the potential effect on the clinical landscape that positive results from the phase 3 study could have.

How do domvanalimab and zimberelimab work alongside chemotherapy to elicit antitumor responses?

: Domvanalimab plus zimberelimab is a combination geared toward providing additional stimulation to T and natural killer [cell] populations, which are important for an antitumor immune response.

Chemotherapy itself [leads to] some immunogenic cell death, which may promote an antitumor immune response. We have a long track record and [data from] multiple phase 3 trials supporting the combination of chemotherapy plus anti–PD-1 [therapy in upper GI cancers]. The question of whether we can further push on the T-cell axis with TIGIT blockade is an open one, and that’s the question that STAR-221 is seeking to answer.

Theoretically, the addition of anti-TIGIT [therapy] may help expand a particularly important immune cell subset—progenitor exhausted T cells—that are important for persistent immune responses. The hope is that PD-1 and TIGIT dual blockade will extend the benefit of immunotherapy to more patients and enhance the durability of response.

Why may TIGIT blockade have a role in upper GI cancers?

It’s certainly an open question, and one that STAR-221 will hopefully answer. We’ve seen some data across tumor types with TIGIT [blockade], and [the history] has been checkered. We’ve seen multiple negative studies in lung cancer, for example; however, upper GI cancers are a different beast. They have inherently different tumor microenvironments and intrinsic immune resistance properties. It’s certainly a concern whether this [approach] will [be effective] in patients with upper GI cancers, but we’re going to get the answer soon.

What data show that this combination could surpass the limitations of SOC agents in the frontline setting for patients with upper GI cancers?

EDGE-Gastric was trying to support the idea of…a phase 3 trial [with an anti-TIGIT approach]. There was no control arm [in EDGE-Gastric], and every patient got the same therapy. We saw a good ORR, but the PFS [data] were even more promising, with a [median] of 12.9 months. This was a significant numerical improvement vs historical controls using FOLFOX plus anti–PD-1 [therapy]. [The results] were promising and—if they hold true—the addition of the anti-TIGIT on top of anti–PD-1 [therapy] might extend [treatment] benefit, but all of the caveats need to be considered. 

This was a single-arm, phase 2 trial of 41 patients, but [the data] are certainly supportive of the idea that there is promise to the strategy of combining FOLFOX with anti–PD-1 and -TIGIT [therapies] in STAR-221.

Are there any notable design characteristics of STAR-221?

It’s a straightforward phase 3 design. Over the last several years, chemotherapy plus immunotherapy has been the standard of care for the vast majority of our patients [with advanced upper GI cancers]. The question is: can we build upon our best standard by adding anti-TIGIT [therapy]? STAR-221 will compare our standard of care, FOLFOX plus nivolumab [Opdivo], with FOLFOX plus domvanalimab and zimberelimab. It is a 1:1 random assignment of approximately 1000 patients.

This is a large phase 3 trial powered to detect a difference and improvement in overall survival, which is the primary end point. There are some prespecified subgroups [based on] what we’ve learned from other phase 3 trials, [which will be] centered around particular PD-L1 strata.

Across the phase 3 trials that have been published, we’ve seen [populations of patients with] a PD-L1 [combined positive score] of greater than 1 and greater than 5 emerge as the main [subgroups] that we need to understand. Those subgroups will help place the data [from STAR-221] in the context of other phase 3 trials.

Were there any barriers to enrollment for STAR-221, given the criteria and existing FDA-approved options in this setting?

The comparator arm is an active combination, and it’s probably our best standard for this patient population. I don’t believe there is a more active control arm that could have been [selected], so that was not a barrier to accrual. The trial is fully accrued, and we’re awaiting the readout.

It accrued quickly because there weren’t a lot of other phase 3 trials in this patient population following the establishment of the chemotherapy plus anti–PD-1 [therapy] as a standard. There was a strong appetite for this trial globally, and now we just need to wait for enough [survival] events to trigger the analyses so we get an understanding of the outcomes, which hopefully we’ll see in the not-too-distant future.

How could positive results from STAR-221 affect the development of domvanalimab and its potential placement among current chemoimmunotherapy regimens in the HER2-negative population?

When we see new patients with stage IV disease, we look at our panel of biomarkers, and we assign them therapies based on that. Patients with microsatellite instability–high disease should clearly receive immunotherapy. Patients with HER2-positive disease get HER2-directed therapies. [Patients in the] HER2-negative population have the option of Claudin-18.2–[directed therapy] if they have Claudin-18.2–positive [disease]. However, for a sizable proportion of these patients, the current standard is chemotherapy plus anti–PD-1 [therapy].

If this STAR-221 is positive, the standard for that population could become chemotherapy plus PD-1 and TIGIT blockade. That would be wonderful for our patients if we’re able to improve the survival even further. I suspect if the trial is positive, it is possible that [this regimen] would change the current standard of chemotherapy plus anti–PD-1 [therapy] to chemotherapy plus anti–PD-1 and -TIGIT [therapy].

Janjigian Y, Oh D, Pelster M, et al. Updates on abstract 433248: EDGE-Gastric arm a1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL.

Gilead and Arcus announce anti-TIGIT domvanalimab plus zimberelimab and chemotherapy exceeded one year of median progression-free survival as a first-line treatment for upper GI cancers. News release. Gilead. June 1, 2024. Accessed June 27, 2025. https://www.gilead.com/news/news-details/2024/gilead-and-arcus-announce-anti-tigit-domvanalimab-plus-zimberelimab-and-chemotherapy-exceeded-one-year-of-median-progression-free-survival-as-a-first-line-treatment-for-upper-gi-cancers

Sam Klempner, MD, discusses the ongoing evaluation of domvanalimab plus zimberelimab and chemotherapy in upper GI cancers.

Domvanalimab-Based Combo Aims to Leverage Anti-TIGIT Mechanism in Upper GI Cancers 

Dr Wainberg on Phase 2 Domvanalimab/Zimberelimab/Chemo Data in Gastric Cancer

“The median PFS in this small cohort was 12.9 months…That’s a signal that warrants further investigation.”

Zev A. Wainberg, MD, MSc, a professor of medicine in the Department of Medicine at UCLA and co-director of the UCLA GI Oncology Program, discussed findings from the phase 2 EDGE-Gastric trial (NCT05329766), which is investigating the efficacy and safety of domvanalimab plus zimberelimab (Sepalizumab) and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) in patients with first-line, locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma.

The largest dataset showing the activity of domvanalimab plus zimberelimab and FOLFOX in patients with newly diagnosed gastric/GEJ/esophageal cancer comes from the EDGE-Gastric trial, Wainberg began. Among 41 evaluable patients in the overall population, where patients were allowed to enroll regardless of PD-L1 status, the overall response rate (ORR) was 59% (95% CI, 42%-74%), including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates of 7%, 51%, 34%, and 5%, respectively. The median duration of response was 12.4 months (95% CI, 9.9-not evaluable). The median progression-free survival (PFS) was 12.9 months (95% CI, 9.8-13.8), and the 12-month PFS rate was 58% (95% CI, 42%-74%).

In the cohort of patients with a PD-L1 tumor activity positivity (TAP) score of at least 5% (n = 16), the ORR rate was 69% (95% CI, 41%-89%), including a CR rate of 6% and a PR rate of 63%; the SD rate was 31%. In the population of patients with a TAP score of less than 5%, the ORR rate was 50% (95% CI, 29%-71%). The respective CR, PR, SD, and PD rates in this population were 4%, 46%, 38%, and 8%.

Overall, these efficacy signals support the continued investigation of domvanalimab plus zimberelimab and chemotherapy in patients with gastric, GEJ, and esophageal cancer, according to Wainberg. The phase 3 STAR-221 study (NCT05568095) is evaluating domvanalimab plus zimberelimab and FOLFOX or CAPOX (capecitabine and oxaliplatin) compared with nivolumab plus FOLFOX or CAPOX in patients with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma.

Videos

Zev A. Wainberg, MD, MSc, discusses data from the EDGE-Gastric trial of domvanalimab plus zimberelimab and FOLFOX in first-line, metastatic gastric cancer.

As the first phase 3 trial to investigate an Fc-silent, anti-TIGIT agent in patients with solid tumors, the STAR-221 study (NCT05568095) may further clarify the therapeutic role of domvanalimab plus zimberelimab (Sepalizumab) and chemotherapy in patients with gastric cancers, potentially reshaping first-line treatment paradigms, particularly for PD-L1–positive disease, according to Kohei Shitara, MD.

STAR-221 is investigating the combination of the TIGIT monoclonal antibody domvanalimab, the PD-1 inhibitor zimberelimab, and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) vs nivolumab (Opdivo) plus FOLFOX or CAPOX in the first-line setting for patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.

 Overall survival (OS) serves as the primary end point. Secondary end points include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), safety, and quality of life outcomes.

The initiation of STAR-221 is based on positive findings from the phase 2 EDGE-Gastric trial (NCT05329766).

 Updated findings from arm A1 of the study showed that in all evaluable patients with first-line, locally advanced unresectable or metastatic gastric/GEJ/esophageal adenocarcinoma (n = 41), at a median follow-up of 13.9 months, the confirmed ORR with domvanalimab plus zimberelimab and FOLFOX was 59% (95% CI, 42%-74%). Among patients with a PD-L1 tumor activity positivity (TAP) score of at least 5% (n = 16), this rate was 69% (95% CI, 41%-89%). Among those with a TAP score of less than 5%, the ORR was 50% (95% CI, 29%-71%).

“Maybe the benefit [will be limited to] patients in the PD-L1–high population, but we should see the actual data [from STAR-221],” Shitara said in an interview with 

®. “If we have positive findings, this may give us important insight about the structure of the antibody and whether Fc-silent or Fc-activated [agents] give us different stories [in the context of] past negative trials.”

In the interview, Shitara discussed the mechanism of action and clinical activity of the TIGIT-targeted agent domvanalimab; preclinical and phase 2 data that support the continued investigation of domvanalimab plus zimberelimab and chemotherapy in patients with gastric/GEJ/esophageal cancers; and the potential clinical implications of results from STAR-221, which may be influenced by PD-L1 status.

Shitara is the director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.

: How do domvanalimab and zimberelimab work alongside chemotherapy to elicit antitumor responses?

: The important target molecule is TIGIT, especially for this combination. TIGIT is an inhibitory checkpoint receptor expressed on various types of immune cells, especially exhausted CD8 cells and regulatory T cells [Tregs], where it usually competes with activating molecules, such as CD20 and CD26, for binding its ligands. If there is TIGIT expression, this usually leads to inhibition of a specific immunophenotype like T cells, Tregs, and natural killer cells. Importantly, [TIGIT] is usually observed with other immune checkpoint molecules, such as PD-1 and LAG-3 [inhibitors]. It is expressed at a relatively later stage of exhaustion. That’s why blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy. This is usually combined with anti–PD-1 and –PD-L1 agents.

An important aspect [of some] TIGIT antibodies is [the] Fc-maintained or Fc-activated [state, which] retains Fc receptor binding capabilities, leading to antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity to deplete TIGIT-expressing immune cells. For example, an Fc-maintained IgG1 antibody may deplete Tregs. This may be good for antitumor response, but it may also increase autoimmune toxicity because of the depletion of Tregs.

Another class of agents is the Fc-silent TIGIT antibody, which is engineered to lack Fc receptor engagement. It doesn’t deplete Tregs—instead, it [mainly] enhances the expansion of effector cells. On the other hand, if Fc is maintained, there is also a risk of depletion of activated effector cells. There are always pros and cons for this kind of structure.

In preclinical studies, there’s a good paper for both classification of Fc-silent and Fc-maintained antibodies. This was published in 

 and supports that Fc-silent IgG1 antibodies for TIGIT may be better compared with Fc-maintained [agents]. However, another group published a different paper in 

 that supports that Fc-activated TIGIT antibodies are better, especially regarding depletion of immunosuppressive cells, like Tregs.

Based on these preclinical studies, TIGIT inhibition is attractive. However, there are 2 types of anti-TIGIT antibodies. Domvanalimab is mainly an Fc-silent IgG1 antibody. This may not deplete inhibitory cells, but [it may] mainly activate exhausted effector cells. Because of its lack of depletion of Tregs, the toxicity profile is expected to be feasible. This is usually combined with the anti–PD-1 [agent] zimberelimab. Zimberelimab is an IgG4 monoclonal antibody [with a mechanism of action] similar to that of nivolumab and pembrolizumab [Keytruda]. This combination has been tested in various clinical trials.

What phase 2 data contributed to the rationale for STAR-221?

This combination’s development is further supported by results from the ongoing EDGE-Gastric trial. This is a first-line gastric cancer trial [planning] to enroll approximately 40 patients to test domvanalimab and zimberelimab in combination with a cytotoxic FOLFOX regimen. Initial data were presented at the 

 and showed an ORR of 59% in the entire population, with a median PFS of 12.9 months. Although the small sample size is a relatively major limitation of the study, [the findings], in direct comparison with [those from] previous pivotal trials like the phase 3 CheckMate 649 [NCT02872116] and KEYNOTE-859 [NCT03675737] studies, suggested an increased ORR and longer median PFS.

The subgroup analysis [data] also support [population] enrichment by PD-L1 status. This TIGIT-directed domvanalimab/zimberelimab/chemotherapy combination seemed to work better in patients with high PD-L1 expression, such as a combined positive score [CPS] or TAP score of 5% or higher. This is in line with our expectations, because TIGIT is usually co-expressed with other checkpoints like PD-1 [T] effector cells. Additionally, the safety profile looks manageable; because of a lack of Treg depletion, autoimmune reactions seem to not be increased.

The phase 3 STAR-221 trial is ongoing to test domvanalimab/zimberelimab in combination with first-line FOLFOX or CAPOX vs the current standard of chemotherapy plus nivolumab in the first-line setting. We needed to test PD-L1 status before patient enrollment. Patients could be enrolled regardless of PD-L1 status, but stratification by PD-L1 status was important, considering the mode of action [of the combination demonstrated in] the subgroup analysis of the phase 2 study. That’s why PD-L1 TAP score was included as one of the stratification factors for the primary end point for OS in this study. Subgroups will also be tested according to TAP score or CPS status. Enrollment [to STAR-221] is completed, and we are waiting for survival follow-up and analysis.

Concerning the current other trials for TIGIT-targeted therapy, unfortunately, no phase 3 trial has shown the benefit of TIGIT inhibitors in any solid tumors. For example, there were negative trials in melanoma, gynecological cancer, and lung cancer. The lung cancer trial showed a borderline benefit of TIGIT inhibition, especially in the PD-L1–positive population.

Although all trials [with TIGIT inhibition] have been negative, there [are opportunities to use TIGIT inhibitors with] different modes of action, especially [regarding] the Fc portion. Previously reported phase 3 trials have almost always applied Fc-maintained or Fc-activated TIGIT inhibitors. STAR-221 is the first study to test an Fc-silent anti-TIGIT antibody. [Therefore], we may observe a difference [in outcomes from this trial] compared with previous negative trials.

How might positive results from STAR-221 affect the development of domvanalimab and the placement of the investigational combination among current chemoimmunotherapy regimens for gastric cancers?

It should depend on the result. If [domvanalimab/zimberelimab/chemotherapy] shows an OS benefit compared with chemotherapy plus nivolumab, it should be at least the standard in some populations. However, this depends on the subgroup analysis [where patients are stratified] by PD-L1 status. If it only shows a benefit in the PD-L1–high population, it should be the treatment used for that population [only].

However, if [the combination] shows an [OS] benefit regardless of PD-L1 status, this is also attractive, because usually patients with low PD-L1 status achieve limited benefit with chemotherapy plus a PD-[L]1 inhibitor. If this trial turns out to be positive, why not test this agent in other types of tumors [beyond those] where previous anti-TIGIT therapy failed to show a survival benefit? It should be interesting.

Chemotherapy/nivolumab is standard, especially for patients with a PD-L1 CPS of 1 or higher. [In patients with a] CPS less than 1, [this combination] didn’t show benefit, but there’s no detrimental effect. The [STAR-221] trial was started before the 

FDA’s Oncologic Drugs Advisory Committee meeting

 about the restriction of [frontline PD-1 inhibitors to patients with HER2-negative, microsatellite-stable gastric/GEJ adenocarcinoma with a PD-L1 CPS greater than 1]. I don’t expect any large barriers or any differences in this [trial] population compared with the general gastric cancer population regarding CPS frequency.

Additionally, the main objective in this study is to see the treatment effect, especially in patients with a CPS or a TAP score of 5% or higher. [CPS] is being monitored during the trial. It does not seem different from the usual frequency [seen in this population], but the exact results should be reported after the analysis.

A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed June 30, 2025. https://www.clinicaltrials.gov/study/NCT05568095

Janjigian Y, Oh D, Pelster M, et al. Updates on abstract 433248: EDGE-Gastric arm a1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1l) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL.

Kohei Shitara, MD, discusses the investigation of domvanalimab plus zimberelimab and chemotherapy in patients with gastric/GEJ/esophageal cancers.

Study of Combined TIGIT/PD-1 Blockade Signals Potential Shift in Gastric Cancer Management

Dr Shitara on the Unique Mechanisms of Action of Domvanalimab Plus Zimberelimab in GI Cancer

"Blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy; this is usually combined with an anti–PD-L1 agent to reduce the exhaustion of T cells. Domvanalimab is an Fc-silent monoclonal antibody, and because of the lack of T-cell depletion, its toxicity profile is expected to be feasible. Zimberelimab's [mechanism of action] is very similar to nivolumab and pembrolizumab, and these combinations have been tested in various clinical trials."

Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East, discussed the rationale for dual immune checkpoint inhibition using domvanalimab and zimberelimab in the treatment of patients with solid tumors, including upper gastrointestinal malignancies. 

Domvanalimab is an investigational anti–TIGIT monoclonal antibody, and zimberelimab is an anti–PD-1 monoclonal antibody. Both agents are being evaluated in combination across several clinical trials targeting cancers with high unmet need.

TIGIT is an inhibitory receptor commonly co-expressed with PD-1 and LAG-3 on exhausted CD8-positive T cells and regulatory T cells (Tregs), particularly in later stages of immune dysfunction. TIGIT blockade is hypothesized to reinvigorate effector immune cells and restore antitumor immunity. Preclinical data suggest that TIGIT inhibition is most effective when combined with PD-1/PD-L1 pathway inhibition, given the overlapping and synergistic mechanisms of T-cell exhaustion and immune evasion.

Shitara emphasized that a key distinction among TIGIT-targeting agents lies in their Fc domain engineering. Some anti-TIGIT antibodies are Fc-competent (Fc-active), retaining the ability to engage Fcγ receptors and mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. This structure allows for potential depletion of TIGIT-expressing Tregs and other immunosuppressive cells. However, this mechanism may also carry a higher risk of depleting activated effector T cells, increasing the likelihood of immune-related toxicities.

Conversely, domvanalimab is an Fc-silent IgG1 antibody, engineered to minimize Fcγ receptor engagement. Shitara noted that this design is expected to preserve effector T-cell function while mitigating immune-mediated adverse effects, making it a favorable candidate for combination immunotherapy. Zimberelimab, the PD-1 inhibitor partner in this combination, is mechanistically analogous to approved agents such as nivolumab (Opvido) and pembrolizumab (Keytruda), he stated.

Preclinical studies offer differing views on Fc domain design in TIGIT antibodies; data from one study published in 

 support the use of Fc-silent constructs for optimal T-cell activation and lower toxicity, whereas a separate 

 publication advocated for Fc-active antibodies based on their ability to deplete suppressive immune cell subsets, Shitara detailed.

Taken together, the combination of domvanalimab and zimberelimab represents a promising Fc-silent immunotherapeutic approach aimed at enhancing antitumor immunity with a favorable safety profile, he said. This strategy is currently under clinical investigation in multiple tumor types, including gastrointestinal cancers, Shitara concluded.

Kohei Shitara, MD, details the mechanisms of action of the investigational therapies domvanalimab and zimberelimab for gastrointestinal cancer. 
 

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